Nebulized imatinib formulations, manufacture, and uses thereof

ABSTRACT

The invention relates to nebulized imatinib formulations, manufacture, and uses thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims the benefit of, and priority to, U.S.Provisional Application Nos. 62/849,054, filed May 16, 2019; 62/849,056,filed May 16, 2019; 62/849,058, filed May 16, 2019; 62/849,059, filedMay 16, 2019; 62/877,575, filed Jul. 23, 2019; 62/942,408, filed Dec. 2,2019; 62/984,037, filed Mar. 2, 2020; and 62/958,481, filed Jan. 8,2020; the content of each of which is hereby incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The invention relates to inhalable imatinib formulations, manufacture,and uses thereof.

BACKGROUND

Pulmonary arterial hypertension (PAH) is a condition involving elevatedblood pressure in the arteries of the lungs with unknown causes and isdifferentiated from systemic hypertension. PAH is a progressive diseasewhere resistance to blood flow increases in the lungs causing damage tothe lungs, the pulmonary vasculature and the heart that can eventuallylead to death. While symptoms are treatable with vasodilators and othermedications, there is no known disease modifying therapy or cure andadvanced cases can eventually require lung transplants.

Imatinib, especially the mesylate salt thereof, is a tyrosine kinaseinhibitor approved for use in treating certain types of cancer.Imatinib's potential to inhibit the tyrosine kinase platelet-derivedgrowth factor receptor (PDGFR) which is highly upregulated in thepulmonary arteries in cases of PAH, led to interest in its use intreating PAH. See, Olschewski, H, 2015, Imatinib for Pulmonary ArterialHypertension—Wonder Drug or Killer Drug? Respiration, 89:513-514,incorporated herein by reference. To that end, studies have beenconducted to determine the potential of imatinib in treating PAH andpatients have been found to respond favorably to such treatment.Unfortunately, an unacceptable amount of severe adverse events includingsubdural hematoma blunted enthusiasm for the drug. Frost, et al., 2015,Long-term safety and efficacy of imatinib in pulmonary arterialhypertension, J Heart Lung Transplant, 34(11):1366-75, incorporatedherein by reference.

SUMMARY

Compositions and methods of the invention address problems withimatinib-based PAH treatments through the use of specializedformulations and delivery mechanisms. Particularly, inhalable imatinibsolutions and suspensions are provided along with methods of deliverysuch formulations through inhalation via a nebulizer. Nebulizers aredrug delivery devices that aerosolize solutions and suspensions forinhalation using compressed gas. By providing imatinib directly to thelungs through nebulized formula, treatment of pulmonary andcardiovascular diseases become feasible without the high-systemicconcentrations of imatinib found to be associated with subdural hematomaor other adverse events. Accordingly, systems and methods of theinvention provide new means of treating PAH and other diseases withoutthe compromises and risks of prior attempts.

Formulations for nebulization may be provided in solution or suspensionform. Imatinib formulations may be used with any type of nebulizer. Forexample, commercially available nebulizers from Vectura Group plc (UK)including jet nebulizers such as the Akita jet nebulizer and the FOXvibrating mesh nebulizer.

Other types of nebulizers contemplated for use with formulations andmethods of the invention include soft mist inhalers and ultrasonic wavenebulizers. Methods and kits of the invention may include dehydrationand reconstitution agents for dehydrating and reconstituting liquidformulations of the invention in a sterile manner for nebulization.

In certain embodiments, formulations may comprise 50% or more imatinibor imatinib salts. Compositions and methods of the invention recognizethat large volumes may be difficult or dangerous for patients to inhaleand that, therefore, minimizing the amount of non-API components in theformulation can improve patient comfort, safety, and compliance byreducing the overall amount of compound that is inhaled while stillproviding a therapeutically effective API concentration in targettissue.

Furthermore, aerodynamic properties important to inhalable drug uptakecan more easily be managed when less of the formulation is required forcarriers or other additives. By providing inhalable formulations withhigh concentrations of imatinib or salts thereof, compositions andmethods of the invention can provide the load-reducing benefitsdiscussed above while still delivering therapeutic results and avoidingthe severe adverse events associated with other drug delivery routes.

Nebulizer-ready formulations of the invention may comprise imatinib orsalts thereof in solution or suspension form in various embodiments.Imatinib suspensions may comprise imatinib particles of entirely oralmost entirely a single crystal form (e.g., greater than 80%, 85%, 90%,95%, 99% or 100% of a single crystal form), thereby allowing forcontrolled and predictable dosing and patient response. In certainembodiments, greater than 95% of imatinib or a salt thereof in theinhalable formulation may be present in a single crystal form.

In certain embodiments inhalable imatinib compounds may be micronizedthrough wet or dry milling (e.g., jet milling) to achieve the desiredparticle size for suspensions for nebulization. Imatinib or appropriatesalts thereof may be micronized to particle sizes of about 0.5 μm toabout 5 μm mass median aerodynamic diameter (MMAD). In certainembodiments, the imatinib free base may be preferred for efficientdelivery of the active moiety to lung tissue. If required, variousexcipients or carriers can be added to imatinib or salts thereof beforeor after micronization depending on application while maintaining arelatively high (e.g., 50% or greater) ratio of the API. For example,carriers, excipients, and conditioners such as lecithin,distearylphosphatidylcholine (DSPC) or other lipid-based carriers, orvarious hydrophilic polymers where they exhibit appropriatephysico-chemical properties may be included. The skilled artisan willappreciate that excipients or carriers are optional and that manyembodiments of the invention do not require excipients or carriers. Incompounds including carriers or excipients, API:carrier ratios may begreater than 50:50, 75:25, or 90:10. Additional ratios are contemplatedas discussed below.

In some embodiments, all or most amorphous imatinib may be excluded fromthe formulation, even after micronization. As noted above, becausecrystal form can be important to drug pharmacokinetics and dosing, aswell as physicochemical stability, avoiding amorphous content can alsobe important to providing predictable and efficient therapy.

Because the inhalable formulations described herein can modulate theuptake of imatinib in the target tissue of the lungs ormicrovasculature, formulations of the invention can be used to treatvarious conditions of the pulmonary cardiovascular system while avoidingthe adverse events associated with higher doses that are administered byother routes of administration that introduce the drug systemicallyprior to reaching the target tissue. For example, compounds and methodsof the invention can be used to treat PAH as well as lung transplantrejection, pulmonary veno-occlusive disease (PVOD) and pulmonaryhypertension secondary to other diseases like heart failure withpreserved ejection fraction (HFpEF) or schistosomiasis. Dose ranges caninclude between about 10 mg to about 100 mg per dose for inhalation on atwice to four times per day schedule. About 0.1 mg to about 80 mg of theactive imatinib compound may then be deposited within the lungs afterinhalation. Because compositions of the invention can have relativelyhigh concentrations of API (e.g., 50% or greater), the above doses canbe achieved with less overall volume of inhalable compared toconventional formulations having 1%-3% API.

In certain embodiments, formulations of the invention can includeprocessing and administration of imatinib in free base form. Free baseimatinib formulations of the invention can retain crystallinity aftermicronization. Accordingly, compounds and methods of the inventioninclude inhalable formulations of free base imatinib.

Aspects of the invention include methods of treating a condition of thepulmonary cardiovascular system. Methods may include providing to asubject a nebulized formulation of imatinib or a salt thereof. Theformulation can include droplets that comprise imatinib or a saltthereof. The droplets may be sized between about 0.5 to about 5 μm.

In certain embodiments formulations may further comprise one or moreexcipients. In some embodiments nebulized formulations may comprisesolubilized imatinib or a salt thereof in solution. The subject can be amammal and, in preferred embodiments, a human. The condition of thepulmonary cardiovascular system may be pulmonary arterial hypertension(PAH). The formulation may be nebulized using a jet nebulizer. In someembodiments the formulation may be nebulized using a vibrating meshnebulizer.

In certain aspects, the invention may include a kit for treating acondition of the pulmonary cardiovascular system, comprising a liquidformulation of imatinib or a salt thereof and a nebulizer. The liquidformulation may be a sterile liquid formulation. The imatinib or a saltthereof may be a dry composition or a salt thereof and the kit maycomprise one or more liquids for reconstituting the imatinib or saltthereof. In various embodiments, the nebulizer may be a jet nebulizer, avibrating mesh nebulizer, a soft mist inhaler, or an ultrasonic wavenebulizer. The dry composition of the imatinib or a salt thereof mayinclude particles of imatinib or a salt thereof. The particles ofimatinib or a salt thereof may have been micronized. The micronizedparticles may be sized about 0.5 to about 5 μm.

In certain embodiments, the formulation may further include one or moreexcipients.

The nebulizer can be operable to generate droplets of the liquidformulation sized between about 0.5 μm and about 5 μm.

In various embodiments, the imatinib or a salt thereof may bepartitioned into two or more volumes, each of the two or more volumescorresponding to a therapeutically effective individual dose fortreating the condition of the pulmonary cardiovascular system. Eachvolume the imatinib or a salt thereof can be a sterile liquidformulation. Kits of the invention may further include a first set ofone or more agents to dehydrate the liquid formulation to produce adried composition of the imatinib or a salt thereof and a second set ofone or more agents to reconstitute the dried composition as a sterileliquid formulation of the imatinib or a salt thereof.

Aspects of the invention may include methods of treating a condition ofthe pulmonary cardiovascular system. Such methods may include providingimatinib or a salt thereof, reconstituting the imatinib or a saltthereof in a sterile solvent to prepare a reconstituted solution ofimatinib or salt thereof, and nebulizing the reconstituted solution. Thereconstituted solution may include one or more excipients. The imatinibor a salt thereof may be a liquid formulation of the imatinib or a saltthereof, and the method can first include dehydrating the liquidformulation to produce a dried composition of the imatinib or a saltthereof. Dehydrating may be accomplished using one or more dehydratingagents.

In certain embodiments, the reconstituting step can include transferringthe sterile solvent from a first to sealed container to a second sealedcontainer comprising the imatinib or salt thereof using a needle ordispensing pin. Nebulizing may include coupling the second sealedcontainer to a nebulizer. In some embodiments, nebulizing can includetransferring the reconstituted solution from the second sealed containerto the nebulizer using a needle or a dispensing pin.

DETAILED DESCRIPTION

The invention relates to inhalable formulations of imatinib and saltsthereof. Specifically, inhalable formulations compatible with nebulizersfor inhalation as well as methods and kits for nebulized imatinibtreatments. Imatinib, as used throughout the application, refers to thefree base compound or salts thereof. Imatinib as the free base has thebelow structure.

The methods and compositions described herein provide greaterconcentrations of imatinib in target lung tissue than obtained withequivalent doses administered orally or through IV.

In various embodiments, imatinib suspensions having the characteristicsdescribed herein (e.g., low polymorphism, high API ratios, and amorphouscontent) can be delivered via inhalation using, for example, anebulizer. While imatinib or salts thereof may be nebulized in solution,imatinib suspensions may offer advantages over solutions in certainembodiments as discussed below.

Nebulizers use oxygen, compressed air, or ultrasonic power to break upsolutions and suspensions into small aerosol droplets that can bedirectly inhaled by a user in need of treatment. Formulations andmethods of the invention may use any known type of nebulizer includingsoft mist inhalers, jet nebulizers, ultrasonic wave nebulizers, andvibrating mesh nebulizers. Jet nebulizers and vibrating mesh nebulizers,for example, are commercially available from Vectura Group plc (UK).

Soft mist inhalers use mechanical energy stored in a spring byuser-actuation to pressurize a liquid container, causing thecontained-liquid to spray out of a nozzle for inhalation in the form ofa soft mist. Soft mist inhalers do not rely on gas propellant orelectrical power for operation. The average droplet size in soft mistinhalers is about 5.8 micrometers.

Jet nebulizers are the most commonly used and may be referred to asatomizers. Jet nebulizers use a compressed gas (e.g., air or oxygen) toaerosolize a liquid medicine when released therethrough at highvelocity. The resulting aerosolized droplets of therapeutic solution orsuspension are then inhaled by a user for treatment. The compressed gasmay be pre-compressed in a storage container or may be compressedon-demand by a compressor in the nebulizer.

Ultrasonic wave nebulizers rely on an electronic oscillator to generatea high frequency ultrasonic wave that, when directed through a reservoirof a therapeutic suspension of solution, aerosolized the medicine forinhalation.

Vibrating mesh nebulizers use the vibration of a membrane havingthousands of holes at the top of the liquid reservoir to aerosolize afine-droplet mist for inhalation. Vibrating mesh nebulizers avoid someof the drawbacks of ultrasonic wave nebulizers, offering more efficientaerosolization with reduced treatment times and less heating of theliquid being nebulized.

In various embodiments, nebulizers used in the invention may includepulsed air flow as described in U.S. Pat. No. 7,866,317, mixed flow ofaerosol and compressed gas as described in U.S. Pat. No. 8,181,644, orother nebulizer features as described in U.S. Pat. Nos. 7,647,928;8,910,625; and 7,891,358; and U.S. Pat. Pub. No. 2015/0174343, thecontent of each of which is incorporated herein by reference. In certainembodiments, concentration of imatinib formulations may be achieved atvarious areas of the lung through manipulation of delayed releasetechnology such as described in U.S. Pat. No. 8,534,277, incorporatedherein by reference.

In certain embodiments, nebulizer formulations may include particlessized and shaped as described in U.S. Pat. No. 8,101,160, or preparedusing methods described in U.S. Pat. Pub. No. 2018/0257084, the contentof each of which is incorporated herein by reference. Formulations andmethods of the invention may include nebulized imatinib administeredusing techniques or in combination with other inhalable compounds asdescribed in U.S. Pat. Nos. 7,928,089; 9,486,427; and 8,834,848 as wellas U.S. Pat. Pub. Nos. 2017/0014424, 2016/0193434, 2010/0297030,2013/0034534, and 2017/0304566, the content of each of which isincorporated herein by reference.

Kits of the invention may include a nebulizer such as those describedabove along with an effective does of a solution or suspension ofimatinib or salts thereof for treating a cardiovascular or pulmonarydisease such as PAH. Kits may include additional materials forreconstituting dry ingredients including imatinib formulations fornebulization in a sterile manner. For example, kits may include sealedcontainers of dry ingredients and sterile solvents (e.g., water) as wellas syringes, needles, dispensing pins, mini-spikes, or other means ofaccessing the solvent within the sealed container and adding it to thedry ingredients. Accordingly, solutions can be reconstituted in asterile manner and then nebulized by users as described herein.

Similarly, methods of dehydrating and otherwise preparing ingredientsfor storage and transportation in a sterile manner are contemplated.Dehydration and lyophilization methods and systems are well known andcan be applied herein in a sterile manner to prepare formulations ofimatinib or salts thereof for storage and shipment prior toreconstitution and nebulization. See Walters, et al., 2014, NextGeneration Drying Technologies for Pharmaceutical Applications, Journalof Pharmaceutical Sciences 103:2673-2695, incorporated herein byreference. Commercial lyophilizers are available, for example, from SPScientific, Warminster, Pa. Dehydration of formulations of the inventionfor nebulizing may be performed using any known dehydration methods oragents such as critical point drying with CO₂ under pressure, solventsubstitution, vacuum, or blow drying (e.g., in a nitrogen atmosphere).

Nebulized doses in high API ratio formulations can make up a relativelyhigh percentage of the overall formulation, allowing them to bedelivered in lower overall volumes than conventional formulations ofbetween 1% and 3% API. Reducing the volume a patient must inhale canincrease patient comfort and compliance, thereby improving results.Additionally, a higher percentage of API content can improve the APIdistribution and blend uniformity. Accordingly, methods and compositionsof the invention allow for treatment of conditions of the pulmonarycardiovascular system (e.g., PAH) with lower doses and less inhalablevolume than would be required in systemic administration, therebylowering the risk of adverse events including subdural hematoma (See,Frost et al.). Thus, the invention provides viable treatment methods forlife threatening diseases that were heretofore too risky for practicalapplication.

In certain embodiments, compounds of the invention include formulationsof imatinib or salts thereof. In preferred embodiments, the free baseimatinib is used in a formulation for inhalation to treat a condition ofthe pulmonary cardiovascular system such as PAH. Certain salt forms arealso contemplated. In various embodiments, imatinib salts that werefound to exhibit suitable thermal stability and few or singlepolymorphic forms include glycollate, isethionate, malonate, tartrate,and malate. Other salt forms contemplated herein are xinafoate, furoate,trifenatate, HCl, sulfate, phosphate, lactate, maleate, fumarate,succinate, adipate, mesylate, and citrate.

When the compounds of the present invention are administered aspharmaceuticals, to humans and mammals, they can be given alone or as apharmaceutical composition containing, for example, 0.1 to 99.5% ofactive ingredient (e.g., imatinib or a salt thereof) in combination witha pharmaceutically acceptable carrier. In preferred embodiments, toreduce inhaled volumes for patients and improve patient outcomes,formulations can comprise at least 50% imatinib or a salt thereof.

In certain embodiments, imatinib formulations of the invention mayinclude one or more excipients. For example, lecithin phospholipids suchas DSPC may be used as an excipient for nebulized inhalation. In certainembodiments, excipients may include various hydrophilic polymers. See,for example, Karolewicz, B., 2016, A review of polymers asmultifunctional excipients in drug dosage form technology, Saudi PharmJ., 24(5):525-536, incorporated herein by reference.

In the high-API-ratio formulations contemplated herein, carriers orexcipients may make up the remainder of the formulation in amounts of50% or less of the overall composition. In certain embodiments,inhalable formulations may have API:carrier ratios of 50:50, 55:45,60:40, 65:35, 70:30, 75:25, 80:20, 85:15, 90:10, or 95:5. Certaininhalable formulations may be pure API with no additional components. Invarious embodiments, formulations may include imatinib or salts thereofas the API in amounts greater than 5%, 10%, 15%, 20%, 25%, 30%, 35%,40%, or 45%. As used herein, API ratios refer to % w/w.

In various embodiments, micronized imatinib and salts thereof retaincrystallinity, even after micronization and suspension for nebulization.For example, imatinib formulations of the invention can include lessthan 50%, less than 25%, less than 20%, less than 10%, less than 9%,less than 8%, less than 7%, less than 6%, less than 5%, less than 4%,less than 3%, less than 2%, or less than 1% amorphous imatinib by mass.In preferred embodiments, formulations of the invention include noobservable amorphous imatinib content. Of particular note is, bysuspending micronized imatinib particles in a solution as opposed tosolubilizing, the desired crystalline form and low amorphous contentobtained during micronization is carried through to nebulization becausethe imatinib crystals are not dissolved in the solution to a significantdegree.

As discussed above, in order to accurately and consistently modelpharmacokinetics of the imatinib formulations for proper dosing, lowpolymorphism is desired. To that end, inhalable formulations of theinvention include imatinib or a salt thereof present in a single crystalform. In various embodiments, imatinib or a salt thereof may be presentat greater than 75%, 80%, 85%, 90%, 95%, or, in preferred embodiments,greater than 99% in a single crystal form by mass. The single crystalform may be, for example, type A or type B in various embodiments.

For nebulized suspensions, micronization and particle diameter may be ofparticular importance for efficient delivery and imatinib may bepreferably micronized to a mass median diameter of 2 μm or less. Thesuspension solution for nebulizer inhalation can be aqueous and dosesmay be divided into individual containers or compartments for sterilestorage prior to use.

Micronized imatinib particle size can range from about 0.5 μm to about 5μm depending on application. In preferred embodiments the size range isabout 1 μm to about 3 μm to achieve deep lung penetration.

In various embodiments, the imatinib formulations of the invention maybe pharmaceutical compositions for use in treating various conditions ofthe pulmonary cardiovascular system, such as PAH. For example, imatinibis a potent inhibitor of the platelet-derived growth factor receptor(PDGFR) and other signaling kinases. Accordingly, the compositions ofthe invention may be used to treat any disease or disorder that involvesinhibition of PDGFR or other kinases sensitive to imatinib.

In certain embodiments, the compositions of the invention may be used totreat PAH. For treatment of PAH or other disorders, a therapeuticallyeffective amount of a pharmaceutical composition of imatinib accordingto the various embodiments described herein can be delivered, viainhalation to deliver the desired amount of imatinib compound to thetarget lung tissue.

Dosages for treating PAH and other conditions of the pulmonarycardiovascular system may be in the range of between about 1 mg to about100 mg per dose for inhalation on once, twice or three times per dayschedule. About 0.1 mg to about 80 mg of the imatinib or salt thereofmay then be deposited within the lung after inhalation. In certainembodiments, about 0.1 to about 1 mg/kg in a dose and may beadministered one to four times a day to obtain the desired therapeuticresults.

In certain embodiments, imatinib formulations of the invention may beused to treat pulmonary hypertension as a result of schistosomiasis.See, for example, Li, et al., 2019, The ABL kinase inhibitor imatinibcauses phenotypic changes and lethality in adult Schistosoma japonicum,Parasitol Res., 118(3):881-890; Graham, et al., 2010,Schistosomiasis-associated pulmonary hypertension: pulmonary vasculardisease: the global perspective, Chest, 137(6 Suppl):20S-29S, thecontent of each of which is incorporated herein by reference.

Imatinib pharmaceutical compositions of the invention may be used totreat lung transplant recipients to prevent organ rejection. See, Keil,et al., 2019, Synergism of imatinib, vatalanib and everolimus in theprevention of chronic lung allograft rejection after lungtransplantation (LTx) in rats, Histol Histopathol, 1:18088, incorporatedherein by reference.

In certain embodiments, pharmaceutical compositions described herein canbe used to treat pulmonary veno-occlusive disease (PVOD). See Sato, etal., 2019, Beneficial Effects of Imatinib in a Patient with SuspectedPulmonary Veno-Occlusive Disease, Tohoku J Exp Med. 2019 February;247(2):69-73, incorporated herein by reference.

For treatment of any conditions of the pulmonary cardiovascular systemfor which imatinib may produce a therapeutic effect, compounds andmethods of the invention may be used to provide greater concentration atthe target lung tissue through inhalation along with consistent,predictable pharmacokinetics afforded by low polymorphism and amorphouscontent. The efficient localization of therapeutic compound at thetarget tissue allows for lower systemic exposure and avoidance of theadverse events associated with prolonged oral administration of imatinibmesylate.

Methods of the invention can include preparation of imatinibformulations. As noted above, imatinib or salts thereof may beadministered via inhalation of nebulized suspensions. Imatinib particlesfor suspension may be obtained via any known method including, inpreferred embodiments, jet milling. Jet milling can be used to grindimatinib and, potentially, various additives (e.g., excipients) using ajet (or jets) of compressed air or gas to force collisions between theparticles as they transit at near sonic velocity around the perimeter ofa toroidal chamber. The size reduction is the result of thehigh-velocity collisions between particles of the process material.Outputs of the jet mill may allow particles to exit the apparatus once adesired size has been reached. As noted herein, desired particle sizemay be in the range of about 0.5 μm to about 5 μm.

In certain embodiments, bulk imatinib may be micronized to the desiredsize for inhalation via wet milling wherein the imatinib particles aresuspended in a slurry and reduced through shearing or impact with agrinding media.

An unexpected finding of the invention is that micronized imatinibobtained using methods of the invention has been found to exhibit noapparent polymorphs other than the designated Type A and very low levelsof amorphous content. Accordingly, this can result in improved stabilityof the drug substance and any drug product upon storage. Single crystalforms such as described may allow for more predictable in vivo behaviorand appropriate dosing can be determined.

In some embodiments an imatinib suspension can be formed. The suspensionmay result from dry micronization followed by suspension of theresulting dry powder or can be obtained as the outcome of a wet millingprocedure. Imatinib suspensions of micronized crystal forms may be usedin nebulized inhalation treatments.

As maintaining a stable solution of crystalline imatinib is important tomany features of the formulations and methods of the invention,formulation methods include manipulation of the suspension to preventdissolution of the imatinib. Aqueous solution factors such as pH, ionicstrength and dispersing agents may be used to obtain a stable suspensionfor nebulized inhalation. For example, the pH of the aqueous solutionmay be adjusted to prevent dissolution.

Additionally, the presence of ions in aqueous solution may tend to ‘saltout’ the imatinib. The solubility of the both imatinib and its mesylatesalt may decrease with salinity. Accordingly, salt in the aqueoussolution may be used to reduce solubility of the imatinib crystals incertain embodiments.

To promote dispersion and thoroughly deagglomerate the imatinibparticles, a dispersing agent or surfactant (e.g., Tween 20 or Tween 80)may be added but should not cause dissolution of the imatinib insuspension.

In certain embodiments, excipients can be added to the suspension beforenebulization. In various embodiments, the excipient may be awater-soluble excipient, such as leucine, dileucine, trileucine,trehalose, mannitol, citrate or acetate. In other embodiment, theexcipient may be a water insoluble excipient, such as lecithin,distearylphosphatidylcholine (DSPC) or limonene. Such insolubleexcipients may be dissolved in a non-aqueous medium that is miscible orimmiscible with water, thereby creating an emulsion. Alternatively, aliposomal dispersion could be created into which the suspended imatinibcould be added and homogenized.

The effective dosage of each agent can readily be determined by theskilled person, having regard to typical factors such as the age,weight, sex and clinical history of the patient. In general, a suitabledaily dose of a compound of the invention will be that amount of thecompound which is the lowest dose effective to produce the desiredtherapeutic effect. Such an effective dose will generally depend uponthe factors described above.

If desired, the effective daily dose of the active compound may beadministered as one, two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

The pharmaceutical compositions of the invention include a“therapeutically effective amount” or a “prophylactically effectiveamount” of one or more of the compounds of the present invention, orfunctional derivatives thereof. An “effective amount” refers to anamount effective, at dosages and for periods of time necessary, toachieve the desired therapeutic result, e.g., a diminishment orprevention of effects associated with PAH. A therapeutically effectiveamount of a compound of the present invention or functional derivativesthereof may vary according to factors such as the disease state, age,sex, and weight of the subject, and the ability of the therapeuticcompound to elicit a desired response in the subject. A therapeuticallyeffective amount is also one in which any toxic or detrimental effectsof the therapeutic agent are outweighed by the therapeuticallybeneficial effects.

A “prophylactically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredprophylactic result. Typically, since a prophylactic dose is used insubjects prior to, or at an earlier stage of disease, theprophylactically effective amount may be less than the therapeuticallyeffective amount. A prophylactically or therapeutically effective amountis also one in which any toxic or detrimental effects of the compoundare outweighed by the beneficial effects.

Dosage regimens may be adjusted to provide the optimum desired response(e.g. a therapeutic or prophylactic response). For example, a singleinhalable bolus may be administered, several divided doses may beadministered over time or the dose may be proportionally reduced orincreased as indicated by the exigency of the therapeutic situation.Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular subject, composition, and mode ofadministration, without being toxic to the patient.

The term “dosage unit” as used herein refers to physically discreteunits suited as unitary dosages for the mammalian subjects to betreated; each unit containing a predetermined quantity of activecompound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on (a) the unique characteristics of the compound, and (b) thelimitations inherent in the art of compounding such an active compoundfor the treatment of sensitivity in individuals.

In some embodiments, therapeutically effective amount can be estimatedinitially either in cell culture assays or in animal models, usuallyrats, non-human primates, mice, rabbits, dogs, or pigs. The animal modelis also used to achieve a desirable concentration range and route ofadministration. Such information can then be used to determine usefuldoses and routes for administration in other subjects. Generally, thetherapeutically effective amount is sufficient to reduce PAH symptoms ina subject. In some embodiments, the therapeutically effective amount issufficient to eliminate PAH symptoms in a subject.

Dosages for a particular patient can be determined by one of ordinaryskill in the art using conventional considerations, (e.g. by means of anappropriate, conventional pharmacological protocol). A physician may,for example, prescribe a relatively low dose at first, subsequentlyincreasing the dose until an appropriate response is obtained. The doseadministered to a patient is sufficient to effect a beneficialtherapeutic response in the patient over time, or, e.g., to reducesymptoms, or other appropriate activity, depending on the application.The dose is determined by the efficacy of the particular formulation,and the activity, stability, or half-life of the compounds of theinvention or functional derivatives thereof, and the condition of thepatient, as well as the body weight or surface area of the patient to betreated. The size of the dose is also determined by the existence,nature, and extent of any adverse side-effects that accompany theadministration of a particular vector, formulation, or the like in aparticular subject. Therapeutic compositions comprising one or morecompounds of the invention or functional derivatives thereof areoptionally tested in one or more appropriate in vitro and/or in vivoanimal models of disease, such as models of PAH, to confirm efficacy,tissue metabolism, and to estimate dosages, according to methods wellknown in the art. In particular, dosages can be initially determined byactivity, stability or other suitable measures of treatment vs.non-treatment (e.g., comparison of treated vs. untreated cells or animalmodels), in a relevant assay. Administration can be accomplished viasingle or divided doses.

In certain embodiments, in which an aqueous suspension is part of themanufacturing process, the aqueous suspension may contain the activematerial in admixture with excipients suitable for the manufacture ofaqueous suspensions. Such excipients are suspending agents dispersing orwetting agents such as a naturally occurring phosphatide, for examplelecithin, or condensation products of an alkylene oxide with fattyacids, for example polyoxyethylene stearate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such apolyoxyethylene with partial esters derived from fatty acids and hexitolanhydrides, for example polyoxyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives, for exampleethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, oneor more flavoring agents, and one or more sweetening agents, such assucrose, mannitol, or trehalose.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives.

The term “pharmaceutical composition” means a composition comprising acompound as described herein and at least one component comprisingpharmaceutically acceptable carriers, diluents, adjuvants, excipients,or vehicles, such as preserving agents, taste-masking agents, fillers,disintegrating agents, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavoring agents, perfuming agents,antibacterial agents, antifungal agents, lubricating agents anddispensing agents, depending on the nature of the mode of administrationand dosage forms. The term “pharmaceutically acceptable carrier” is usedto mean any carrier, diluent, adjuvant, excipient, or vehicle, asdescribed herein.

The term “pharmaceutically acceptable” means it is, within the scope ofsound medical judgment, suitable for use in contact with the cells ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, and are commensurate with a reasonablebenefit/risk ratio.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, web content,have been made throughout this disclosure. All such documents are herebyincorporated herein by reference in their entirety for all purposes.

EQUIVALENTS

Various modifications of the invention and many further embodimentsthereof, in addition to those shown and described herein, will becomeapparent to those skilled in the art from the full content of thisdocument, including references to the scientific and patent literaturecited herein. The subject matter herein contains important information,exemplification and guidance that can be adapted to the practice of thisinvention in its various embodiments and equivalents thereof.

What is claimed is:
 1. A method of treating a condition of the pulmonarycardiovascular system, the method comprising providing to a subject anebulized formulation of imatinib or a salt thereof.
 2. The method ofclaim 1, wherein the nebulized formulation comprises droplets thatcomprise imatinib or a salt thereof.
 3. The method of claim 2, whereinthe droplets comprise a size of about 0.5 μm to about 5 μm.
 4. Themethod of claim 1, wherein the formulation further comprises one or moreexcipients.
 5. The method of claim 1, wherein the formulation comprisessolubilized imatinib or a salt thereof.
 6. The method of claim 1,wherein the subject is a human.
 7. The method of claim 1, wherein thecondition of the pulmonary cardiovascular system is pulmonary arterialhypertension (PAH).
 8. The method of claim 1, wherein the formulation isnebulized using a jet nebulizer.
 9. The method of claim 1, wherein theformulation is nebulized using a vibrating mesh nebulizer.
 10. A kit fortreating a condition of the pulmonary cardiovascular system, comprisingimatinib or a salt thereof and a nebulizer.
 11. The kit of claim 10,wherein the imatinib or a salt thereof is a liquid formulation of theimatinib or a salt thereof.
 12. The kit of claim 10, wherein the liquidformulation is a sterile liquid formulation.
 13. The kit of claim 10,wherein the imatinib or a salt thereof is a dry composition of theimatinib or a salt thereof and the kit further comprises one or moreliquids to reconstitute the imatinib or a salt thereof into a liquidformulation of the imatinib or a salt thereof.
 14. The kit of claim 13,wherein the liquid formulation is a sterile liquid formulation.
 15. Thekit of claim 13, wherein the dry composition of the imatinib or a saltthereof comprises particles of imatinib or a salt thereof.
 16. The kitof claim 15 wherein the particles of imatinib or a salt thereof havebeen micronized.
 17. The kit of claim 16, wherein the particles comprisea size of about 0.5 to about 5 μm.
 18. The kit of claim 10, wherein theformulation further comprises one or more excipients.
 19. The kit ofclaim 10, wherein the nebulizer is operable to generate droplets of theliquid formulation sized between about 0.5 μm and about 5 μm.
 20. Thekit of claim 10, wherein the subject is a human.
 21. The kit of claim10, wherein the condition of the pulmonary cardiovascular system ispulmonary arterial hypertension (PAH).
 22. The kit of claim 10, whereinthe nebulizer is a jet nebulizer.
 23. The kit of claim 10, wherein thenebulizer is a vibrating mesh nebulizer.
 24. The kit of claim 10,wherein the imatinib or a salt thereof is partitioned into two or morevolumes, each of the two or more volumes corresponding to atherapeutically effective individual dose for treating the condition ofthe pulmonary cardiovascular system.
 25. The kit of claim 24, whereineach volume the imatinib or a salt thereof is a sterile liquidformulation.
 26. The kit of claim 10, wherein the imatinib or a saltthereof is a liquid formulation of the imatinib or a salt thereof andthe kit further comprises: a first set of one or more agents todehydrate the liquid formulation to produce a dried composition of theimatinib or a salt thereof; and a second set of one or more agents toreconstitute the dried composition as a sterile liquid formulation ofthe imatinib or a salt thereof.
 27. A method of treating a condition ofthe pulmonary cardiovascular system, the method comprising: providingimatinib or a salt thereof; reconstituting the imatinib or a saltthereof in a sterile solvent to prepare a reconstituted solution ofimatinib or a salt thereof; and nebulizing the reconstituted solution.28. The method of claim 27, wherein the reconstituted solution furthercomprises one or more excipients.
 29. The method of claim 27, whereinthe imatinib or a salt thereof is a dried composition of the imatinib ora salt thereof.
 30. The method of claim 27, wherein the imatinib or asalt thereof is a liquid formulation of the imatinib or a salt thereof,and the method first comprises dehydrating the liquid formulation toproduce a dried composition of the imatinib or a salt thereof.
 31. Themethod of claim 30, wherein dehydrating is accomplished using one ormore dehydrating agents.
 32. The method of claim 27, wherein thereconstituting step comprises transferring the sterile solvent from afirst to sealed container to a second sealed container comprising theimatinib or salt thereof using a needle or dispensing pin.
 33. Themethod of claim 32, wherein the nebulizing step comprises coupling thesecond sealed container to a nebulizer.
 34. The method of claim 33,wherein the nebulizing step comprises transferring the reconstitutedsolution from the second sealed container to the nebulizer using aneedle or a dispensing pin.